This project involves the synthesis and biochemical/biophysical investigations of novel ring-expanded ("fat") purine and ring-contracted ("slim") pyrimidine nucleosides and nucleotides. With judicious atom insertion at the ring loci and functionalization of the ring periphery, these "fat" and "slim" nucleotides are potentially capable of Watson-Crick base-pair hydrogen bonding with appropriate pyrimidine partners. Because of their unique structures, these aberrant nucleotides are excellent probes for nucleic acid structure, function, and metabolism. Our studies are directed toward a) synthesizing various "fat" and "slim" nucleosides and nucleotides and constructing double helices, b) investigations of base-pairing and stacking interactions of homo- and heteropolymer duplexes incorporated with "fat" or "slim" nucleotides, c) explorations of structural and spatial limitations of formation of double helices, as well as of helical structure, stability and conformations, d) biochemical investigations to determine the potential of "fat" and "slim" nucleosides and nucleotides to act as substrates or inhibitors of various enzymes of nucleic acid metabolism. Using these analogs, base-mispairing accompanied by considerable deviation of base-sugar bond deviation from the natural array can potentially result in chain termination of the developing DNA during reverse transcription of a retroviral RNA genome such as that of the human immunodeficiency virus (HIV), the etiologic agent causing the acquired immunodeficiency syndrome (AIDS). "Fat" and "slim" nucleosides and nucleotides, are, therefore, potential chain terminators operating by this mechanism. Low-resolution and high-resolution FAB-MS has been used extensively to characterize these synthetic products.